Biomedical subjects

Hitomi Namiki

Publications and source records attributed to Hitomi Namiki.

3 recordsLinked to original sources

PubMed2005

Effect of chronic administration of ritonavir on function of cytochrome P450 3A and P-glycoprotein in rats.

Ritonavir (RTV) is well known as an inhibitor of many drugs that are metabolized by cytochrome P450 (CYP) 3A or fluxed via P-glycoprotein (Pgp), although it is also reported that RTV is a potent inducer for them. In this study, to elucidate these contradictory phenomena, functional changes of CYP3A or Pgp during chronic administration of RTV were examined in rats. After pretreatment with RTV for indicated days (day 3-day 14), rats were used in the experiments. The area under the plasma drug concentration vs. time curve (AUC(0-infinity)) after oral administration of RTV (20 mg/kg) to these rats showed an RTV-treatment period-dependent decrease, and the mean AUC(0-infinity) of RTV in Day 14 rats decreased significantly by 57% as compared to the control. The AUC(0-infinity) after intravenous (i.v.) administration of RTV to Day 3 and Day 5 rats increased significantly by 28% and 22%, respectively, while there were no significant changes in the AUC(0-infinity) in Day 7 and Day 14 rats as compared to the control. As for i.v. administration of erythromycin (EM) or midazolam (MDZ) to RTV-treated rats, the AUC(0-infinity)in Day 3 and Day 5 rats increased significantly as compared to the control, while in Day 7 rats and rifampicin-treated rats, the AUC(0-infinity) of EM decreased significantly by 82% and 42%, respectively, as compared to the control. For MDZ, there were no significant changes in the AUC(0-infinity) in Day 7 or Day 14 rats. After i.v. administration of rhodamine123 (Rho123), the excretion clearances from blood circulation to the intestinal lumen and the biliary excretion clearances in Day 14 rats increased markedly by 2.2-fold and 2.6-fold as compared to the control. It has been confirmed that RTV is not only a potent inhibitor but also a potent inducer of CYP3A, and that RTV is a potent inducer of intestinal Pgp. This property of RTV is responsible for regulating the oral bioavailability of drugs that are mediated by CYP3A and Pgp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

In vivo effects of cyclosporin A and ketoconazole on the pharmacokinetics of representative substrates for P-glycoprotein and cytochrome P450 (CYP) 3A in rats.

In this study, the in vivo effects of cyclosporin A (CsA) and ketoconazole (KCZ), which are used as inhibitors of P-glycoprotein (Pgp) and cytochrome P450 (CYP) 3A, respectively, on the pharmacokinetics of rhodamine 123 (Rho123), nelfinavir (NFV) and erythromycin (EM) were evaluated in rats. The biliary excretion clearance (Clbile) of a known Pgp substrate, Rho123, after intravenous pretreatment with CsA or KCZ (0-20 mg/kg after i.v. administration) showed maximum reduction by 85.6 or 54.1%, respectively, suggesting that the inhibitory potency of KCZ is about half that of Pgp in the liver. Without pretreatment with CsA or KCZ, the clearance ratio of Clbile relative to the total body clearances of Rho123, NFV and EM was 10.5, 0.07 and 31.1%, respectively. After CsA pretreatment, these ratios decreased markedly in a manner dependent on the dose of CsA, while after CZ pretreatment the clearance ratios of NFV and EM increased significantly in a manner dependent on the dose of KCZ. However, in the liver, the contribution of Pgp to the changes in the pharmacokinetic parameters of Rho123, NFV and EM after intravenous administration was much less than that of CYP3A. The portal levels of Rho123 and EM but not NFV after intra-loop administration in the presence of 10 microM CsA in the jejunal loop increased significantly, while in the presence of 25 microM KCZ in the jejunal loop, the portal levels of those substrates showed no notable change as compared to the control levels. In conclusion, KCZ had dual potency to inhibit CYP3A and Pgp, and its inhibitory potency for Pgp was half that of CsA in the rat liver. In addition, metabolism via CYP3A contributed more significantly to the clearance of these substrates that did excretion via Pgp in the liver. In the small intestine, the contribution of Pgp is a more important factor in determining the oral bioavailability of EM than metabolism via CYP enzymes. The elimination of NFV is mainly dependent on liver metabolism via CYP3A, and the Pgp efflux mechanism in the liver and intestine did not contribute as importantly to the oral bioavailability of NFV under in vivo conditions, although NFV has been demonstrated to be a substrate of Pgp under in vitro conditions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Evaluation of factors to decrease plasma concentration of an HIV protease inhibitor, saquinavir in ethanol-treated rats.

Although alcohol consumption is a factor in which the bioavailability of saquinavir (SQV) are retarded, the cause for this phenomenon remains to be uncertain. In the presence study, we examined factors to decrease plasma concentration of SQV in ethanol-treated rats. The ethanol-treated rats were prepared by making them freely access to 15% ethanol solution for 14 d (Day 14 rats). The exsorption clearance of SQV from the blood circulation to the jejunal lumen in the Day 14 rats increased by 6-fold as compared to ethanol non-treated (NT) rats. In the presence of 25 microM ketoconazole (KCZ) or 10 microM cyclosporin A (CsA) in the jejunal lumen, the plasma concentration of SQV in the portal vein increased significantly, and this effect of 10 microM CsA was superior to that of 25 microM KCZ. The biliary excretion clearance of SQV in Day 14 rats also increased by 1.8-fold as compared to that in the NT rats. The metabolic clearance rate (V(max)/K(m)) of SQV in the intestinal microsomes from the Day 14 rats increased significantly, while in the liver microsomes the V(max)/K(m) did not change. The phase II metabolism processes in the Day 14 rats based on UDP-glucuronosyltransferases and gultathion-S-tnrasferase activities were activated, however, they were not likely to be one of factors to decrease the bioavailability of oral SQV, because CYP3A activity in the liver and intestine was not activated to such an extent and SQV itself was not conjugated. These observations suggest that a main possible factor to explain the reducing effect on the SQV oral bioavailability during ethanol consumption is an enhanced efflux of SQV at the intestine and liver, where it is suggested that functional enhancement or excessive expression of P-glycoprotein is caused by ethanol consumption.

ATP Binding Cassette Transporter, Subfamily B, Mem↗